Mount Sinai ADRC (Sano): OVERALL ? Research Summary Alzheimer's disease (AD) is a major health threat to the nation and the world causing great human pain and economic loss. While some advances have been made in detection and raising awareness, finding treatments has remained unsuccessful in spite of decades of research. To date, efforts have focused on defining the disease by a narrow characterization of end-stage pathology, using restrictive samples and technologies that systematically exclude the diversity of the disease. This approach has led to multiple failures, resulting in scant progress on the therapeutic front. With this backdrop, the Mount Sinai Alzheimer's Disease Research Center (MSADRC), with its history of success in therapeutic development dedicates itself anew to identify and develop effective approaches to treating AD. Co-located in Manhattan on the Mount Sinai campus and in the Bronx at the James J Peters Veterans Administration Medical Center, we bring the strength of two premiere institutions to the mission of finding a treatment for AD. This application builds on these institutional strengths including systems- based approaches to scientific inquiry, using the computational tools to mine big data and our established expertise in recruiting diverse populations. We propose as our theme ?Understanding disease heterogeneity to optimize therapeutic approaches to treat and cure Alzheimer's disease? as it aligns our strengths with the implementation areas and milestones of the National Alzheimer's Project Act (NAPA). We propose 7 cores (Administrative, Clinical, Biomarker, Genetics, Neuropathology, Data, and Outreach) and a Research Education Component, all of which have outstanding leadership reflecting newly recruited faculty as well investigators with established histories at the MSADRC. Using the collaborative efforts of the Clinical and Outreach Core, enhanced by novel methods of patient engagement through the electronic medical records at both locations, we propose to expand and maintain a cohort of 450 diverse individuals, 40% of whom will be from under-represented minorities, all receiving annual clinical evaluations, genetic analysis, and blood biomarker collection. The Genetics Core will collect genetics data on all, generate GWAS, and will obtain plasma samples for established biomarkers and proteomics on this diverse cohort. Our new Biomarker Core, supported by new philanthropy and existing research efforts will obtain structural and functional imaging on all patients, and molecular phenotyping with CSF biomarkers or molecular imaging on at least 50% of the cohort, capturing its full diversity. The Neuropathology Core, expanding collection beyond brain to other relevant tissues and body fluids obtained at autopsy, will allow the preparation of relevant brain regions for unbiased systematic sampling (stereology) and autopsy-derived specimens for iPS, multiomics, microbiome, and exosome studies. The Data Core, enhanced by the addition of the Senior Associate Dean for Scientific Computing and Data Science as Core Co-Leader, will expand the capacity to integrate and share the Core's resources to facilitate interdisciplinary collaborations and create an environment that fosters innovative approaches to finding treatments and cures.